Evidence of Associations between Cytokine Genes and Subjective Reports of Sleep Disturbance in Oncology Patients and Their Family Caregivers

The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS) obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5%) and higher sleep disturbance (11.5%). Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB) predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.     

Population study of tender point counts and pain as evidence of fibromyalgia.

OBJECTIVE--To determine the relation between tender points, complaints of pain, and symptoms of depression, fatigue, and sleep quality in the general population. DESIGN--Two stage cross sectional study with an initial questionnaire about pain to classify those eligible for an examination of tender points. SETTING--Two general practices in north west England. SUBJECTS--Stratified random sample of adults from age-sex registers. Of the responders, 250 were selected for examination of tender points on the basis of their reported pain complaints; 177 subsequently participated. MAIN OUTCOME MEASURES--Tender point count (0 to 18) grouped into four categories with the highest (> or = 11) corresponding to the criteria of the American College of Rheumatology for fibromyalgia. Assessment of pain (chronic widespread, regional, none). Measures of depression, fatigue, and difficulty with sleeping. RESULTS--Women had a higher median tender point count (six) than did men (three). Counts were higher in those with pain than in those who had no pain and in those with widespread compared with regional pain. Most subjects with chronic widespread pain, however, had fewer than 11 tender points (27/45; 60%). Two people with counts of 11 or more were in the group reporting no pain. Mean symptom scores for depression, fatigue, and sleep problems increased as the tender point count rose (P value for trend < 0.001). These trends were independent of pain complaints. CONCLUSIONS--Tender points are a measure of general distress. They are related to pain complaints but are separately associated with fatigue and depression. Sleep problems are associated with tender points, although prospective studies are needed to determine whether they cause tenderness to develop. Fibromyalgia does not seem to be a distinct disease entity.     

The Association between Chronic Widespread Musculoskeletal Pain,Depression and Fatigue Is Genetically Mediated

Background

Chronic widespread muscoloskeletal pain (CWP) is prevalent in the general population and associated with high health care costs, so understanding the risk factors for chronic pain is important for both those affected and for society. In the present study we investigated the underlying etiological structure of CWP to understand better the association between the major clinical features of fatigue, depression and dihydroepiandrosterone sulphate (DHEAS) using a multivariate twin design.

Methodology/Principle Findings

Data were available in 463 UK female twin pairs including CWP status and information on depression, chronic fatigue and serum DHEAS levels. High to moderate heritabilities for all phenotypes were obtained (42.58% to 74.24%). The highest phenotypic correlation was observed between fatigue and CWP (r = 0.45), and the highest genetic correlation between CWP and fatigue (r_g = 0.78). Structural equation modeling revealed the AE Cholesky model to provide the best model of the observed data. In this model, two additive genetic factors could be detected loading heavily on CWP—A2 explaining 40% of the variance and A3 20%. The factor loading heaviest on DHEAS showed only a small loading on the other phenotypes and none on fatigue at all. Furthermore, one distinct non-shared environmental factor loading specifically on CWP—but not on any of the other phenotypes—could be detected suggesting that the association between CWP and the other phenotypes is due only to genetic factors.

Conclusions/Significance

Our results suggest that CWP and its associated features share a genetic predisposition but that they are relatively distinct in their environmental determinants.     

Association between an interleukin 1 receptor,type I promoter polymorphism and self-reported attentional function in women with breast cancer

Subgroups of patients with breast cancer may be at greater risk for cytokine-induced changes in cognitive function after diagnosis and during treatment. The purposes of this study were to identify subgroups of patients with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) predictors of subgroup membership. Self-reported attentional function was evaluated in 397 patients with breast cancer using the Attentional Function Index before surgery and for six months after surgery (i.e., seven time points). Using growth mixture modeling, three attentional function latent classes were identified: High (41.6%), Moderate (25.4%), and Low-moderate (33.0%). Patients in the Low-moderate class were significantly younger than those in the High class, with more comorbidities and lower functional status than the other two classes. No differences were found among the classes in years of education, race/ethnicity, or other clinical characteristics. DNA was recovered from 302 patients’ samples. Eighty-two single nucleotide polymorphisms among 15 candidate genes were included in the genetic association analyses. After controlling for age, comorbidities, functional status, and population stratification due to race/ethnicity, IL1R1 rs949963 remained a significant genotypic predictor of class membership in the multivariable model. Carrying the rare “A” allele (i.e., GA + AA) was associated with a twofold increase in the odds of belonging to a lower attentional function class (OR: 1.98; 95% CI: 1.18, 3.30; p = .009). Findings provide evidence of subgroups of women with breast cancer who report distinct trajectories of attentional function and of a genetic association between subgroup membership and an IL1R1 promoter polymorphism.     

Effects of Sleep Fragmentation and Chronic Latent Viral Infection on Behavior and Inflammation in Mice

Many chronic diseases are associated with both fatigue and disrupted or nonrestorative sleep. In addition, so-called ‘sickness behaviors’ (for example, anorexia, anhedonia, reduced social interaction, fatigue) are common during infectious and inflammatory disease and have been linked to facets of the immune response. To study these relationships, we used murine gammaherpesvirus (MuGHV), a natural pathogen of wild rodents that provides an experimental model for studying the pathophysiology of an Epstein-Barr (EBV)-like γ-herpesvirus infection in mice. We exposed male and female C57BL/6J mice that were either uninfected or latently infected with MuGHV to either sleep fragmentation (SF) or control conditions and measured the effects on behavior and markers of inflammation. Exposure of infected male mice to SF during the normal somnolent (light) phase significantly reduced locomotor activity during the subsequent active phase, despite an intervening 6-h rest period. Infection was associated with significant increases in lung IFNγ and CXC motif ligand (CXCL) 10 in both male and female mice. In both infected and uninfected male mice, exposure to SF was associated with lower levels of IL1β and C-C motif ligand (CCL) 3 in lung. Exposure of infected female mice to SF led to reductions in lung IL2, CXCL1, and CCL 3. Thus, compared with control conditions, SF was generally associated with lower concentrations of various cytokines in lung. These findings, together with our previous work, indicate that complex interactions among several host factors likely contribute to the behavioral and inflammatory changes associated with viral infection and sleep disruption even in a well-controlled mouse model.Abbreviations: CCL, CC motif ligand; CXCL, CXC motif ligand; CW, consolidated walking; DE, disk environment; EBV, Epstein–Barr virus; HC, home cage; MuGHV, murine gammaherpesvius; SF, sleep fragmentationSo-called ‘sickness behaviors’ (for example, fatigue, anorexia, anhedonia, reduced social interaction) have often been linked to facets of the host response to immune or inflammatory challenge. During chronic infections or other inflammatory conditions, the continually primed host immune response is likely to create a powerful and unrelenting stimulus for these debilitating symptoms in some patients. Epstein–Barr virus (EBV) is a ubiquitous human gammaherpesvirus that causes acute disease, establishes life-long latency, and is associated with the common syndrome of infectious mononucleosis and with other conditions. Infection with or reactivation of EBV in humans is often associated with fatigue and excessive sleepiness.^{1,20,24,46,53} These and related symptoms could be mediated in part by immune activation or dysfunction, neural–endocrine homeostatic imbalance, or both, as produced secondary to the acute and chronic viral infection.^7,36 Studies demonstrating that antibodies to latent EBV proteins are elevated in some patients with chronic fatigue have led to speculation that 1) the synthesis of these viral proteins reflects stress-related reactivation of latent virus,^17,23,31 and 2) although host responses to reactivation may abort complete viral replication, the viral proteins themselves or the resultant host immune response may trigger or exacerbate fatigue.¹⁸Because gammaherpesviruses coevolved with their host species, they are highly species-specific, and infections of animals with EBV have rarely been reported. However, murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that provides an experimental model for studying the pathophysiology of an EBV-like gammaherpesvirus in laboratory mice, which are a permissive host.^15,16,32 After intranasal infection of immunocompetent mice with MuGHV, pulmonary viral titers peak between days 6 to 9, and lytic virus is cleared from the lung in about 10 to 14 d.¹⁴ Like other herpesviruses, MuGHV can maintain lifelong latency in its host. Latent virus is established in lung within days after infection.¹⁴ Spleen, lymph nodes, and bone marrow also harbor latent virus, primarily in B lymphocytes.^13-15,44 The number of latently infected cells peaks at approximately day 14 after infection and then declines rapidly, such that viral load at 4 wk after infection is barely above the limits of detection.⁶ Immunologic features of MuGHV infection resemble the infectious mononucleosis stage of EBV infection.^5,9,15,51 Key common features of EBV and MuGHV infections include splenomegaly and lymphocytosis.Our past work has shown that mice develop significant clinical illness during the acute stage of MuGHV infection and show elevated behavioral sensitivity to challenge with LPS during the chronic–latent stage of infection.³³ In our more recent work,⁴⁹ male C57BL/6J and BALB/cByJ mice that were placed in a novel cage containing its normal inhabitant during the initial 6 h of the light (somnolent) phase were less active during the subsequent dark (active) phase, independent of infection status and despite a 6-h light-phase interval that provided time for recovery sleep after the period of socially induced arousal. In these mice, changes in inflammatory mediators were complex, with both independent and interactive effects of infection status, mouse strain, and exposure to the perturbation.⁴⁹ However, the chemokine CXC motif ligand (CXCL) 10 was consistently elevated in the lung of latently infected mice. Exposure to an unfamiliar mouse for 6 h also was associated with higher pulmonary concentrations of CXCL10, IL1β, granulocyte colony-stimulating factor, and monocyte chemoattractant protein 1 at 12 h after exposure, independent of infection status. These data indicate that exposure of mice to a social challenge is associated with 1) a pulmonary inflammatory response and 2) reduced activity that could represent fatigue, depression, or other facets of sickness behavior; both of these effects are at least in part independent of mouse strain and latent MuGHV infection.To further investigate the effect of common mild stressors on behavior and inflammation in association with latent viral infection, we exposed mice to sleep fragmentation (SF). We selected SF as a perturbation in light of the common incidence of disturbed or shortened sleep in the human population. In our laboratory, we induce SF by placing mice on a rotating disk that requires them to engage in frequent but brief epochs of walking. Therefore, we also evaluated 2 control conditions: consolidated walking (CW) and exposure to the disk environment with minimal rotation (DE).     

Fatigue in Type 2 Diabetes: Impact on Quality of Life and Predictors

Fatigue is a persistent symptom, impacting quality of life (QoL) and functional status in people with type 2 diabetes, yet the symptom of fatigue has not been fully explored. The purpose of this study was to explore the relationship between fatigue, QoL functional status and to investigate the predictors of fatigue. These possible predictors included body mass index (BMI), Hemoglobin A1C (HbA1C), sleep quality, pain, number of complications from diabetes, years since diagnosis and depression. Forty-eight individuals with type 2 diabetes (22 females, 26 males; 59.66±7.24 years of age; 10.45 ±7.38 years since diagnosis) participated in the study. Fatigue was assessed by using Multidimensional Fatigue Inventory (MFI-20). Other outcomes included: QoL (Audit of Diabetes Dependent QoL), and functional status (6 minute walk test), BMI, HbA1c, sleep (Pittsburg sleep quality index, PSQI), pain (Visual Analog Scale), number of complications, years since diagnosis, and depression (Beck’s depression Inventory-2). The Pearson correlation analysis followed by multivariable linear regression model was used. Fatigue was negatively related to quality of life and functional status. Multivariable linear regression analysis revealed sleep, pain and BMI as the independent predictors of fatigue signaling the presence of physiological (sleep, pain, BMI) phenomenon that could undermine health outcomes.     

Behavioral Perturbation and Sleep in Healthy and Virus-Infected Inbred Mice

Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that has been studied extensively in terms of host immune responses to herpesviruses during acute infection, latency, and reactivation from latency. Although herpesvirus infections in people can be associated with fatigue and excessive sleepiness during both acute and latent infection, MuGHV has not been assessed extensively as a model for studying the behavioral consequences of chronic latent herpesvirus infections. To assess MuGHV infection as a model for evaluating fatigue and assessing potential mechanisms that underlie the exacerbation of fatigue during chronic viral disease, we evaluated sleep, temperature, and activity after exposure of healthy and latently MuGHV-infected mice to sleep fragmentation and social interaction. Neither treatment nor infection significantly affected temperature. However, at some time points, latently infected mice that underwent sleep fragmentation had less locomotor activity and more slow-wave sleep than did mice exposed to social interaction. In addition, delta-wave amplitude during slow-wave sleep was lower in infected mice exposed to sleep fragmentation compared with uninfected mice exposed to the same treatment. Both reduced locomotor activity and increased time asleep could indicate fatigue in infected mice after sleep fragmentation; reduced delta-wave amplitude during slow-wave sleep indicates a light plane of sleep from which subjects would be aroused easily. Identifying the mechanisms that underlie sleep responses of mice with chronic latent MuGHV infection may increase our understanding of fatigue during infections and eventually contribute to improving the quality of life for people with chronic viral infections.Abbreviations: CFS, chronic fatigue syndrome; DWA, delta-wave amplitude; EBV, Epstein–Barr virus; MuGHV, murine γ-herpesvirus; REMS, rapid-eye-movement sleep; SF, sleep fragmentation; SI, social interaction; SWS, slow-wave sleepEpstein–Barr virus (EBV) is a ubiquitous human γ-herpesvirus that causes acute disease, establishes life-long latency and is associated with the common syndrome of infectious mononucleosis. Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that provides an experimental animal model for studying the pathophysiology of an EBV-like gammaherpesvirus.^10,27 A comparison of MuGHV strain 68 (MuGHV68) infection in bank voles (a natural host) and laboratory mice (Mus musculus) using in vivo luciferase imaging and classic virologic methods showed that the 2 host species have quantitative differences in the magnitude of the infection yet exhibit comparable patterns of viral replication and sites of viral latency.¹² These findings support using MuGHV68 and Mus musculus for the study of gammaherpesvirus pathogenesis. Although MuGHV has been studied extensively with regard to host immune responses to herpesviruses during acute infection, latency, and reactivation from latency,^10,27 it has not been assessed extensively as a model for the study of the behavioral consequences of chronic latent herpesvirus infections.EBV infection in humans is often associated with fatigue and excessive sleepiness during both acute and latent phases of infection.^{1,16,19,38,43,44} Many people similarly experience fatigue in association with other chronic medical conditions that have either specific viral etiologies (for example, hepatitis C, HIV) or symptoms suggestive of viral infections (for example, chronic fatigue syndrome (CFS), fibromyalgia syndrome).^3,21,23 Acute viral infections, persistent viral infections, and reactivation of latent virus may trigger or exacerbate fatigue.^15,29,35 Furthermore, exacerbation of fatigue in response to various physiologic and psychologic challenges is prominent in many disease conditions associated with chronic fatigue. For example, exercise is reported to precipitate or exacerbate fatigue or malaise in persons with CFS,^2,26 and CFS both reduces activity and blunts the circadian rhythm of activity in patients.⁴² In addition, stressful life events are reported to precipitate CFS and to exacerbate fatigue in persons with CFS,^6,37and stress can be a factor in reactivation of latent EBV and other herpesviruses.¹⁵ Fatigue, like other so-called ‘sickness behaviors’ (for example, anorexia, anhedonia, reduced social interaction), has been linked causally to various cytokines that are facets of the immune response.⁷ Therefore, the host immune response to chronic infection or inflammation is likely to create a powerful and unrelenting stimulus for fatigue.Human fatigue can be viewed as continued performance of essential activities (for example, employment, care-giving) with curtailment of nonessential, voluntary, or recreational activities.³² Similarly, fatigue in mice can be defined operationally as a reduction in voluntary activity (that is, wheel running) as compared with essential activity (that is, locomotion in the cage to obtain food and water).^28,30,33 Problems with sleep can either reflect or contribute to fatigue. For example, excessive sleep may reflect fatigue associated with other causes, whereas poor sleep or inadequate amounts of sleep may cause fatigue.Mice inoculated with MuGHV develop changes in sleep and activity that may indicate fatigue. On days 7 through 11 after inoculation (that is, at times associated with the peak lytic infection and its resolution), infected mice show hypothermia, increased somnolence, and reduced running-wheel activity during the dark (active) phase of the diurnal cycle as well as reduced food intake and body weight.²⁸ These measures all return to normal during days 11 through 30 after inoculation, as the virus enters the latent phase.²⁸ After this time, these behavioral indicators of fatigue can again be elicited by challenging mice with LPS. In uninfected mice, LPS administration induces modest and relatively transient (that is, less than 18 h) hypothermia, reduced running-wheel activity, and alterations in sleep.²⁸ In contrast, mice with latent MuGHV infection develop prolonged hypothermia, hypoactivity, hypersomnolence, and fragmented sleep, all of which persist for as long as 5 d after LPS administration.²⁸ This duration is consistent with the time reported for viral reactivation from latency in MuGHV-infected mice treated with LPS.¹⁴ Therefore, as compared with uninfected mice, mice with latent infections appear to show a greater magnitude and duration of LPS-induced behavioral perturbations that may reflect fatigue, perhaps in association with virus reactivation.To further assess MuGHV infection as a model system for evaluation of fatigue and assessment of potential mechanisms that underlie exacerbation of fatigue during chronic viral disease, we extended our previous work^28,40 by evaluating sleep, temperature, and activity after exposure of uninfected and latently infected mice to sleep fragmentation (SF) and social interaction (SI), both of which are likely to create behavioral stress.     

Identifying patterns of eating and physical activity in children: a latent class analysis of obesity risk

We used latent class analysis (LCA) to identify heterogeneous subgroups with respect to behavioral obesity risk factors in a sample of 4th grade children (n = 997) residing in Southern California. Multiple dimensions assessing physical activity, eating and sedentary behavior, and weight perceptions were explored. A set of 11 latent class indicators were used in the analysis. The final model yielded a five-class solution: "High-sedentary, high-fat/high-sugar (HF/HS) snacks, not weight conscious," "dieting without exercise, weight conscious," "high-sedentary, HF/HS snacks, weight conscious," "active, healthy eating," and "low healthy, snack food, inactive, not weight conscious." The results suggested distinct subtypes of children with respect to obesity-related risk behaviors. Ethnicity, gender, and a socioeconomic status proxy variable significantly predicted the above latent classes. Overweight or obese weight status was determined based on the Centers for Disease Control and Prevention BMI (kg/m2)-for-age-and-sex percentile (overweight, 85th percentile ≤ BMI < 95th percentile; obese, 95th percentile ≤ BMI). The identified latent subgroup membership, in turn, was associated with the children's weight categories. The results suggest that intervention programs could be refined or targeted based on children's characteristics to promote effective pediatric obesity interventions.     

Suicidal Ideation and Suicide Attempts in Anxious or Depressed Family Caregivers of Patients with Cancer: A Nationwide Survey in Korea

Purpose

To describe the prevalence of suicidal ideation and suicide attempts in family caregivers (FCs) of patients with cancer and to identify the factors associated with suicidal ideation and suicide attempts in FCs with anxiety or depression.

Methods

A national, multicenter survey administered to 897 FCs asked questions concerning suicidal ideation and suicide attempts during the previous year and assessed anxiety, depression, socio–demographic factors, caregiving burden, patient factors, and quality of life (QOL).

Results

A total of 17.7% FCs reported suicidal ideation, and 2.8% had attempted suicide during the previous year. Among FCs with anxiety, 31.9% had suicidal ideation and 4.7% attempted suicide; the corresponding values for FCs with depression were 20.4% and 3.3%, respectively. Compared with FCs without anxiety and depression, FCs with anxiety or depression showed a higher adjusted odds ratios (aOR) for suicidal ideation (aOR  = 4.07 and 1.93, respectively) and attempts (OR  = 3.00 and 2.43, respectively). Among FCs with anxiety or depression, being female, unmarried, unemployed during caregiving, and having a low QOL were associated with increased odds of suicidal ideation. FCs with anxiety who became unemployed during caregiving constituted a high-risk group for suicide. Being unmarried and having a low QOL with respect to financial matters were associated with increased suicide attempts among FCs with depression.

Conclusion

FCs with anxiety or depression were at high risk of suicide. Interventions to enhance social support and to improve perceived QOL may help prevent suicide and manage suicidal ideation in FCs with anxiety or depression.     

Latent Cluster Analysis of ALS Phenotypes Identifies Prognostically Differing Groups

Background

Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes.

Methods

Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method.

Results

The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001).

Conclusion

The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research.     

ASSOCIATIONS BETWEEN CHRONOTYPE,SLEEP QUALITY,SUICIDALITY, AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH MAJOR DEPRESSION AND HEALTHY CONTROLS

Research interest concerning associations between sleep characteristics and suicidality in psychopathology has been growing. However, possible linkages of suicidality to sleep characteristics in terms of sleep quality and chronotypes among depressive patients have not been well documented. In the current study, the authors investigated the possible effects of sleep quality and chronotype on the severity of depressive symptoms and suicide risk in patients with depressive disorder and healthy controls. The study was conducted on 80 patients clinically diagnosed with major depression and 80 healthy subjects who were demographically matched with the patient group. All participants completed a questionnaire package containing self-report measures, including the Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Morningness–Eveningness Questionnaire (MEQ), and Suicide Ideation Scale (SIS), and subjects were interviewed with the suicidality section of the Mini-International Neuropsychiatric Interview (MINI). Results are as follows: (a) logistic regression analyses revealed that poor sleep quality and depression symptom severity significantly predicted onset of major depression; (b) morningness-type circadian rhythm may play as a significant relief factor after onset of major depression; (c) sleep variables of chronotype and sleep quality did not significantly predict suicide ideation after controlling for depressive symptoms in the major depression group; and (d) suicide ideation and poor sleep quality were antecedents of depression symptom severity in patients with major depression, and in healthy controls. Findings are discussed under the theoretical assumptions concerning possible relations between chronotype, sleep quality, depression, and suicidality. (Author correspondence: dryavuzselvi@yahoo.com)     

Effectiveness of enhanced cognitive behavior therapy for bulimia nervosa in Japan: a randomized controlled trial protocol

Although fatigue is a common and distressing symptom in cancer survivors, the mechanism of fatigue is not fully understood. Therefore, this study aims to investigate the relation between the fatigue and mindfulness of breast cancer survivors using anxiety, depression, pain, loneliness, and sleep disturbance as mediators. Path analysis was performed to examine direct and indirect associations between mindfulness and fatigue. Participants were breast cancer survivors who visited a breast surgery department at a university hospital in Japan for hormonal therapy or regular check-ups after treatment. The questionnaire measured cancer-related-fatigue, mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance. Demographic and clinical characteristics were collected from medical records. Two-hundred and seventy-nine breast cancer survivors were registered, of which 259 answered the questionnaire. Ten respondents with incomplete questionnaire data were excluded, resulting in 249 participants for the analyses. Our final model fit the data well (goodness of fit index = .993; adjusted goodness of fit index = .966; comparative fit index = .999; root mean square error of approximation = .016). Mindfulness, anxiety, depression, pain, loneliness, and sleep disturbance were related to fatigue, and mindfulness had the most influence on fatigue (β = − .52). Mindfulness affected fatigue not only directly but also indirectly through anxiety, depression, pain, loneliness, and sleep disturbance. The study model helps to explain the process by which mindfulness affects fatigue. Our results suggest that mindfulness has both direct and indirect effects on the fatigue of breast cancer survivors and that mindfulness can be used to more effectively reduce their fatigue. It also suggests that health care professionals should be aware of factors such as anxiety, depression, pain, loneliness, and sleep disturbance in their care for fatigue of breast cancer survivors. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN number. 000027720) on June 12, 2017.     

The Association between Daytime Napping and Cognitive Functioning in Chronic Fatigue Syndrome

Objectives

The precise relationship between sleep and physical and mental functioning in chronic fatigue syndrome (CFS) has not been examined directly, nor has the impact of daytime napping. This study aimed to examine self-reported sleep in patients with CFS and explore whether sleep quality and daytime napping, specific patient characteristics (gender, illness length) and levels of anxiety and depression, predicted daytime fatigue severity, levels of daytime sleepiness and cognitive functioning, all key dimensions of the illness experience.

Methods

118 adults meeting the 1994 CDC case criteria for CFS completed a standardised sleep diary over 14 days. Momentary functional assessments of fatigue, sleepiness, cognition and mood were completed by patients as part of usual care. Levels of daytime functioning and disability were quantified using symptom assessment tools, measuring fatigue (Chalder Fatigue Scale), sleepiness (Epworth Sleepiness Scale), cognitive functioning (Trail Making Test, Cognitive Failures Questionnaire), and mood (Hospital Anxiety and Depression Scale).

Results

Hierarchical Regressions demonstrated that a shorter time since diagnosis, higher depression and longer wake time after sleep onset predicted 23.4% of the variance in fatigue severity (p <.001). Being male, higher depression and more afternoon naps predicted 25.6% of the variance in objective cognitive dysfunction (p <.001). Higher anxiety and depression and morning napping predicted 32.2% of the variance in subjective cognitive dysfunction (p <.001). When patients were classified into groups of mild and moderate sleepiness, those with longer daytime naps, those who mainly napped in the afternoon, and those with higher levels of anxiety, were more likely to be in the moderately sleepy group.

Conclusions

Napping, particularly in the afternoon is associated with poorer cognitive functioning and more daytime sleepiness in CFS. These findings have clinical implications for symptom management strategies.     

Musculoskeletal Pain as a Marker of Health Quality. Findings from the Epidemiological Sleep Study among the Adult Population of S?o Paulo City

BackgroundWe are witnessing the growth of urban populations, particularly in the developing world. São Paulo, the largest city in South America, continues to grow, and this growth is dramatically effecting the environment and human health. The aim of this study was to estimate the point prevalence of chronic pain in São Paulo city dwellers and to explore the influence of aspects related to urbanicity.MethodsA two-stage cluster randomized sample included 1100 individuals of the city of Sao Paulo, representing the population proportionally in terms of gender, age and social classes in 2007. For this observational cross-sectional study, the household sample was interviewed using validated questionnaires for sociodemographic aspects, the Beck inventories for anxiety and depression, the WHOQoL-REF for quality of life, the Chalder Fatigue Scale. Musculoskeletal pain was defined as diffuse pain or pain located in the back, joints or limbs. Data regarding sleep complaints and polysomnography were obtained from the Epidemiologic Sleep Study conducted in São Paulo city in 2007.ResultsThe prevalence estimate of chronic musculoskeletal pain was approximately 27%, with a female/male ratio of approximately 2.6/1. The predictors were being in the age-range of 30–39 years, low socioeconomic and schooling levels, obesity, sedentarism, fatigue, non-restorative sleep, daytime sleepiness, poor sleep quality, poor life quality, anxiety and depression symptoms. Psychological wellbeing was the main discriminator between responders with chronic musculoskeletal pain and the controls, followed by depression for the participants with poor psychological wellbeing, and fatigue, for the remaining ones. Insomnia syndrome was the third-level discriminator for those with fatigue, whereas sleep quality for those without fatigue.ConclusionsMusculoskeletal pain was frequently reported by São Paulo city dwellers and its correlates with psychological and sleep aspects are suggestive of a response to urbanicity.

Trial Registration

ClinicalTrials.gov NCT00596713     

Interpreting and Testing Interactions in Conditional Mixture Models

Mixture modeling applications in psychology often include covariates to explain class membership and aid in construct validation of the latent classification variable. These applications tend to use between-class models involving only main effects of predictors. However, a variety of developmental theories posit interactions among risk and protective variables in predicting membership in trajectory classes or behavioral symptom profiles. This article bridges this disconnect between substantive theory and methodological practice by presenting and comparing two approaches for testing interactive effects of predictors on class membership: product term (PT) and multiple group (MG) approaches. For each approach, we discuss alternative interpretation strategies involving predicted probabilities and odds ratios; we also discuss when the approaches provide equivalent inferences. Published longitudinal and cross-sectional mixture model applications that had originally allowed for only additive effects on class membership are re-analyzed to illustrate the testing and interpretation of interactive effects on class membership using both PT and MG approaches.     

Poor Sleep in Patients with Multiple Sclerosis

Background

Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients.

Methods

A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients.

Results

MS patients reported a higher mean global PSQI score than controls (8.6 vs. 6.3, p = 0.001), and 67.1% of the MS patients compared to 43.9% of the controls (p = 0.002) were poor sleepers. Pain (p = 0.02), fatigue (p = 0.001), depression (p = 0.01) and female gender (p = 0.04) were associated with sleep disturbance. Multivariate analyses showed that female gender (p = 0.02), use of immunotherapy (p = 005) and a high psychological burden of MS (p = 0.001) were associated with poor sleep among MS patients.

Conclusions

Poor sleep is common in patients with MS. Early identification and treatment of modifiable risk factors may improve sleep and quality of life in MS.     

Sleep Trajectories of Women Undergoing Elective Cesarean Section: Effects on Body Weight and Psychological Well-Being

Background

After cesarean section (CS), women may be at great risk for sleep disturbance, but little is known about temporal changes in their sleep patterns and characteristics. We had two aims: 1) to identify distinct classes of sleep-disturbance trajectories in women considering elective CS from third-trimester pregnancy to 6 months post-CS and 2) to examine associations of sleep trajectories with body mass index (BMI), depressive symptoms, and fatigue scores.

Methods

We analyzed data from a prospective cohort study of 139 Taiwanese pregnant women who elected CS. Sleep components were assessed using the Pittsburgh Sleep Quality Index in third-trimester pregnancy, 1 day, 1 week, 1 month, and 6 months post-CS. Data were collected on depressive symptoms, fatigue symptoms, and BMI. Sleep-quality trajectories were identified by group-based trajectory modeling.

Results

We identified three distinct trajectories: stable poor sleep (50 women, 36.0%), progressively worse sleep (67 women, 48.2%), and persistently poor sleep (22 women, 15.8%). Poor sleep was significantly associated with pre-pregnancy BMI and more baseline (third-trimester pregnancy) depressive and fatigue symptoms. At 6 months post-CS, women classified as progressively worse or persistently poor sleepers showed a trend toward higher BMI (p<0.03), more depressive symptoms (p<0.001), and higher fatigue scores (p<0.001) than those with stable poor sleep.

Conclusions

Women had three distinct sleep-disturbance trajectories before and after elective CS. These poor-sleep courses were associated with BMI and psychological well-being. Our findings suggest a need to continuously assess sleep quality among women considering elective CS and up to 6 months post-CS.     

Evaluating the association between latent classes and competing risks outcomes with multiphenotype data

Latent class analysis is an intuitive tool to characterize disease phenotype heterogeneity. With data more frequently collected on multiple phenotypes in chronic disease studies, it is of rising interest to investigate how the latent classes embedded in one phenotype are related to another phenotype. Motivated by a cohort with mild cognitive impairment (MCI) from the Uniform Data Set (UDS), we propose and study a time-dependent structural model to evaluate the association between latent classes and competing risk outcomes that are subject to missing failure types. We develop a two-step estimation procedure which circumvents latent class membership assignment and is rigorously justified in terms of accounting for the uncertainty in classifying latent classes. The new method also properly addresses the realistic complications for competing risks outcomes, including random censoring and missing failure types. The asymptotic properties of the resulting estimator are established. Given that the standard bootstrapping inference is not feasible in the current problem setting, we develop analytical inference procedures, which are easy to implement. Our simulation studies demonstrate the advantages of the proposed method over benchmark approaches. We present an application to the MCI data from UDS, which uncovers a detailed picture of the neuropathological relevance of the baseline MCI subgroups.     

Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness

Gulf War Illness (GWI) is a multi‐symptom disorder with features characteristic of persistent sickness behavior. Among conditions encountered in the Gulf War (GW) theater were physiological stressors (e.g., heat/cold/physical activity/sleep deprivation), prophylactic treatment with the reversible AChE inhibitor, pyridostigmine bromide (PB), the insect repellent, N,N‐diethyl‐meta‐toluamide (DEET), and potentially the nerve agent, sarin. Prior exposure to the anti‐inflammatory glucocorticoid, corticosterone (CORT), at levels associated with high physiological stress, can paradoxically prime the CNS to produce a robust proinflammatory response to neurotoxicants and systemic inflammation; such neuroinflammatory effects can be associated with sickness behavior. Here, we examined whether CORT primed the CNS to mount neuroinflammatory responses to GW exposures as a potential model of GWI. Male C57BL/6 mice were treated with chronic (14 days) PB/ DEET, subchronic (7–14 days) CORT, and acute exposure (day 15) to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. DFP alone caused marked brain‐wide neuroinflammation assessed by qPCR of tumor necrosis factor‐α, IL6, chemokine (C‐C motif) ligand 2, IL‐1β, leukemia inhibitory factor, and oncostatin M. Pre‐treatment with high physiological levels of CORT greatly augmented (up to 300‐fold) the neuroinflammatory responses to DFP. Anti‐inflammatory pre‐treatment with minocycline suppressed many proinflammatory responses to CORT+DFP. Our findings are suggestive of a possible critical, yet unrecognized interaction between the stressor/environment of the GW theater and agent exposure(s) unique to this war. Such exposures may in fact prime the CNS to amplify future neuroinflammatory responses to pathogens, injury, or toxicity. Such occurrences could potentially result in the prolonged episodes of sickness behavior observed in GWI.